Herpes simplex

Meet the patient

A 3-year-old is brought in with two days of high fever, drooling, and refusal to eat or drink. Her gums are swollen, red, and bleeding on contact, with clusters of tiny vesicles and yellow-grey ulcers scattered across her tongue, buccal mucosa and lips. Her mother thinks it is hand-foot-and-mouth; the Antibiotic course did nothing. It is primary herpetic gingivostomatitis, and the real risk is dehydration.[12][24]

Hold two questions for every HSV presentation: what is the site and is it primary or recurrent? (these set the severity and the dose) and is this one of the emergencies? — eczema herpeticum, the dendritic ulcer, encephalitis, or a vesicle on a neonate. The morphology is always the same; what changes is the host and the stakes.[6]

One virus, one morphology, a dozen faces

HSV produces the same lesion everywhere — grouped vesicles on an erythematous base, evolving to pustules, erosions and crusts — and a different emergency at every site. Two types cause clinically indistinguishable mucocutaneous disease but differ in epidemiology and where they like to hide.[1][2]

The "HSV-1 above the belt, HSV-2 below it" teaching is now a false dichotomy — and examiners test exactly this. As orolabial HSV-1 exposure in childhood has fallen in high-income countries, HSV-1 has become the leading cause of primary genital herpes in adults under 30, while HSV-2 has plateaued or slightly declined. Either type can land at any mucocutaneous site by direct contact, and recurrence follows the site of primary infection more than the virus type.[19][20][3]

[2]

The confession worth making: despite three decades of nucleoside-analogue therapy, there is no cure and no licensed vaccine. Treatment reduces severity, duration and transmission, but the latent virus in the ganglion is permanent. Manage expectations honestly — suppression is control, not eradication.[2][4]

The latency lifecycle — infect, ascend, wait, return

The reason HSV is lifelong is anatomical: the virus climbs into a sensory ganglion and sits there as a silent episome. Every recurrence, and most transmission, comes out of that hidden reservoir.[1]

The virion attaches through glycoproteins gB and gC to heparan sulphate, then gD binds nectin-1 or HVEM to trigger fusion, and gH-gL switches on gB to complete entry. In the epithelial cell the lytic cycle runs about 18–20 hours and destroys the keratinocyte — ballooning degeneration, Cowdry type A intranuclear inclusions, multinucleated giant cells — which is exactly what makes the vesicle and the positive Tzanck smear.[1]

In the sensory neuron the virus changes programme: latency-associated transcripts (LATs) are transcribed while the immediate-early genes are silenced under repressive heterochromatin, and the genome persists as an episome for the life of the host. Reactivation is fired by UV light, fever, stress, menstruation, local trauma and immunosuppression — all of which activate neuronal stress pathways — sending virus back down the axon to the same dermatome, which is why recurrences keep returning to the identical spot.[1]

Asymptomatic shedding is the single largest driver of transmission, and the fact patients find hardest to believe. Most HSV-2 transmission to a discordant partner happens during days with no visible lesion at all — shedding is detectable by PCR on 10–20 percent of days. This is why suppressive therapy, not just avoiding sex during a flare, is the transmission-reduction strategy.[4][21]

The histology of an active lesion gives the 3 Ms every candidate must name — multinucleation, margination of chromatin, and moulding of nuclei — with Cowdry type A eosinophilic intranuclear inclusions. Note the trap: a positive Tzanck smear confirms a herpesvirus, not which one — it cannot separate HSV-1 from HSV-2, VZV or CMV.[2][6]

How common, and who sheds

HSV is one of the most ubiquitous human infections — roughly two-thirds of adults carry HSV-1.[19][20]

[1] [4]

Read the lesions — the syndromes by site

The morphology never changes; the site decides the syndrome, the severity, and the trap. A grouped vesicle on the vermilion is a cold sore; the same lesion on a neonate is a catastrophe.[6][3]

• Primary gingivostomatitis — a child aged 6 months to 5 years with abrupt high fever, refusal to feed, drooling, and tender cervical nodes; swollen bleeding gums with vesicles then ulcers on tongue, buccal mucosa, lips and vermilion. Resolves in 10–14 days; dehydration is the acute danger.[12]
• Recurrent herpes labialis — a prodrome of tingling or burning for 6–24 hours, then a tight vesicle cluster on the vermilion border, crusting in 2–3 days and healing in 7–10. Two to three episodes a year, same spot, triggered by UV, fever, stress, menstruation or dental work.[6][18]
• Primary genital herpes — 3–14 days after contact, bilateral painful vesicles and shallow ulcers with fever, headache, dysuria (even retention from sacral radiculopathy) and tender inguinal nodes. HSV-2 primary is the severe one; HSV-1 genital is milder and recurs less.[3][4]
• Recurrent genital herpes — shorter, milder, usually unilateral; 1–12 vesicles healing in 5–10 days. HSV-2 reactivates 4–6 times a year, HSV-1 once or twice.[4][21]

Herpetic whitlow is the finger lesion with the one inviolable rule: never incise it. A painful, swollen, erythematous distal finger with grouped vesiculopustules on the volar pad, classically in a dentist, anaesthetist or thumb-sucking child, after 2–7 days incubation. Incising risks dissemination, secondary infection and prolonged healing — it resolves over 2–3 weeks with antivirals. Distinguish it from bacterial paronychia by the disproportionate pain, the vesicles, and the absence of pus.[10][11][12]

Herpes gladiatorum is the contact-sport HSV — grouped vesicles on the head, neck or trunk of a wrestler or rugby player, with explosive team outbreaks. Management is barrier checks, covering or excluding athletes until lesions crust, and antivirals; NCAA-level screening protocols exist.[13][14]

The four emergencies — where HSV kills or blinds

Four HSV presentations are time-critical, and each has a single non-negotiable first move. Miss any one and a patient is harmed.[5][7][16][22]

Eczema herpeticum (Kaposi varicelliform eruption) is disseminated HSV in atopic or otherwise damaged skin, and it is a dermatological emergency. The signature is monomorphic "punched-out" 2–4 mm circular erosions — not vesicles — erupting across flared eczema, Darier disease, pemphigus or a burn, with fever, malaise and lymphadenopathy, often co-infected with Staphylococcus aureus. A defect in innate antiviral immunity (reduced interferon-alpha and gamma, defective plasmacytoid dendritic cells, filaggrin loss-of-function) underlies the susceptibility. Treat with systemic aciclovir — IV if widespread or febrile — plus anti-staphylococcal cover, and admit the unwell child.[7][8][9]

HSV keratitis is the leading cause of infectious blindness in industrialised countries. A painful red eye with photophobia and reduced corneal sensation shows a dendritic ulcer — branching epithelial defects with terminal end bulbs on fluorescein staining under cobalt-blue light. Same-day ophthalmology and topical antiviral (ganciclovir 0.15 percent gel or aciclovir 3 percent ointment), plus oral valaciclovir for stromal disease. Never give topical corticosteroid monotherapy — it melts an epithelial dendrite into geographic ulceration.[22]

HSV encephalitis is the commonest sporadic fatal viral encephalitis in adults — HSV-1 in about 95 percent — presenting over hours to days with fever, altered consciousness, personality change and temporal-lobe seizures. MRI shows temporal-lobe oedema and haemorrhage; CSF shows lymphocytic pleocytosis. Untreated mortality exceeds 70 percent. The rule: start empirical IV aciclovir 10 mg/kg every 8 hours before the CSF PCR returns — do not wait for imaging or a result.[1][2]

Neonatal herpes is the feared complication of maternal genital HSV — acquired peripartum in 85 percent — and presents as SEM (skin, eye, mouth), CNS (encephalitis, seizures, bulging fontanelle), or disseminated (hepatitis, pneumonitis, DIC, shock) disease by the Kimberlin classification. Any vesicle, sepsis-like illness or seizure in a neonate is HSV until proven otherwise. Start IV aciclovir 20 mg/kg every 8 hours on suspicion.[16]

Investigations — PCR first, always

The diagnosis is clinical in a classic recurrent cold sore or genital recurrence; laboratory confirmation is essential everywhere else — atypical lesions, primary disease, neonates, the eye, encephalitis, eczema herpeticum, and the immunocompromised.[5][6]

[5]

The test to name first in every stem is vesicle-fluid PCR. It outperforms culture at every lesion stage, is unaffected by crusting, and gives a type. CSF PCR is essential in suspected encephalitis (a single early negative does not exclude it — repeat in 48–72 hours if suspicion persists). In a neonate, sample all three compartments at once — blood, CSF and surface swabs (eye, mouth, nasopharynx, rectum) — because surface PCR alone misses disseminated or CNS disease.[5][6][16]

When an immunocompromised patient's HSV is not responding after 7–14 days of adequate aciclovir, send antiviral susceptibility testing (plaque reduction or sequencing of UL23 thymidine kinase and UL30 polymerase) — resistance is coming.[15]

Management — three pillars, three timings

HSV treatment is one decision tree: is it the first episode, a recurrence, or suppression? The drugs are the same — aciclovir, valaciclovir (its better-absorbed prodrug), and famciclovir — but the dose and duration change with the timing. All three need viral thymidine kinase to activate to the triphosphate that inhibits DNA polymerase. Give slow IV infusion with hydration to avoid aciclovir crystal nephropathy, and renal-adjust when eGFR is low.[5]

The benefit of antivirals is greatest started within 72 hours of onset, especially in severe primary disease. The three oral regimens for a first episode:[5][24]

[5] [5] [18] [5] [21] [1]

Offer suppression for at least six recurrences a year, severe recurrences, immunocompromise, recurrent erythema multiforme triggered by HSV, and pregnancy from 36 weeks. Suppression cuts clinical recurrence by 70–80 percent and subclinical shedding. The Corey 2004 NEJM trial is the evidence that examiners want: once-daily valaciclovir 500 mg cut HSV-2 transmission to discordant partners by about 48 percent over eight months — the basis for offering suppression to serodiscordant couples.[4][21]

Aciclovir resistance — when the workhorse fails

Aciclovir resistance is almost exclusively an immunocompromised-host problem, and it is thymidine-kinase-mediated — which is why escalating the aciclovir dose never overcomes it. The virus loses or alters TK (UL23), so the drug is never activated to its triphosphate; occasionally the polymerase (UL30) mutates. Suspect it in an HIV, transplant or chemotherapy patient with large chronic verrucous or ulcerative lesions failing to respond after 7–14 days of adequate aciclovir.[15]

The rescue drug is IV foscarnet 40 mg/kg every 8–12 hours, with hydration and renal monitoring; alternatives are IV cidofovir and topical cidofovir or imiquimod. Send susceptibility testing to confirm. The recurring trainee error is to keep pushing the aciclovir dose higher — the mechanism makes that futile.[15]

Special populations — pregnancy, neonates, the immunocompromised

Pregnancy turns HSV from a nuisance into an obstetric emergency, because neonatal herpes is the catastrophe. The risk is primary genital HSV near delivery — which is why caesarean delivery is recommended before rupture of membranes for primary lesions at onset of labour. For recurrent genital HSV with no active lesions, vaginal delivery is acceptable, and suppresses with valaciclovir 500 mg BD from 36 weeks (ACOG Practice Bulletin 220, RCOG) to cut shedding, recurrence at delivery, and caesareans done for HSV. Maternal disseminated HSV (hepatitis, encephalitis) is rare but severe and needs IV aciclovir and ICU support.[17][23]

Neonatal HSV is a tiered emergency. Start IV aciclovir 20 mg/kg every 8 hours immediately on suspicion — 14 days for SEM, 21 days for CNS or disseminated disease — then oral suppression 300 mg/m² three times daily for 6 months after CNS or disseminated disease, which improves neurodevelopmental outcome. Treat concurrent bacterial sepsis until cultures clear, and arrange ophthalmology, audiology and neurodevelopmental follow-up. Where maternal primary genital HSV is suspected, avoid scalp electrodes and alert the neonatal team before birth.[16]

The immunocompromised host (transplant, HIV with CD4 under 200, biologic or JAK-inhibitor therapy) gets severe, recurrent, atypical and resistant HSV. Use higher-dose oral aciclovir 800 mg five times daily or IV aciclovir 10 mg/kg every 8 hours for severe disease, empirical low-dose suppression during the highest-risk window, and send resistance testing early when response is poor.[15]

Atopic dermatitis patients carry the eczema-herpeticum risk — counsel them to present early with any sudden febrile deterioration of their eczema, and consider suppressive valaciclovir in those with a prior eczema herpeticum episode and frequent severe flares.[7][8]

Differential diagnosis — the named traps

Three mimics cause most mislabels; each has a single discriminator the examiner wants.[5][6]

[5]

The classic trap — the mouth: calling every recurrent oral ulcer "aphthous." HSV has a vesicular phase first, favours keratinised mucosa (vermilion, hard palate, attached gingiva), and recurs at the same site. Aphthae are ulcers from the outset on movable mucosa with no vesicles. When unsure in an immunocompromised patient, swab for HSV PCR before reaching for steroids.[6]

The classic trap — the finger: incising a herpetic whitlow as bacterial paronychia. The grouped vesicles, the pain out of proportion to the swelling, and the absence of pus separate them — and the scalpel makes herpetic whitlow disseminate.[10][11]

Regional deltas

[5]

How HSV patients come to harm — the preventable list

• Incising a herpetic whitlow as bacterial paronychia, seeding dissemination and prolonged healing.[10]
• Calling eczema herpeticum "infected eczema" in a febrile atopic child and missing disseminated HSV — the monomorphic punched-out erosions are the tell.[7][8]
• Putting topical corticosteroid on a red eye that is a dendritic ulcer — geographic melt and visual loss.[22]
• Waiting for the CSF PCR before starting IV aciclovir in suspected encephalitis — hours cost neurons.[1]
• Sending a neonate with vesicles home as "a rash" — any vesicle in a neonate is HSV until proven otherwise.[16]
• Forgetting suppressive valaciclovir from 36 weeks in a woman with recurrent genital HSV — it halves caesareans done for HSV.[17][23]
• Escalating aciclovir doses in resistant immunocompromised disease — TK-mediated resistance needs foscarnet, not more aciclovir.[15]
• Leaving a persistent indurated genital ulcer unbiopsied in a high-risk patient — SCC, syphilis and chancroid hide there.[5]

Prognosis and disposition

Recurrent oral and genital herpes are lifelong, with recurrences gradually decreasing in severity over years and rarely threatening the immunocompetent adult. Severity escalates sharply in eczema herpeticum, neonatal CNS and disseminated disease, HSV encephalitis, and aciclovir-resistant disease in immunocompromise. Even treated, neonatal CNS disease leaves roughly 30 percent of survivors with neurodevelopmental impairment, and disseminated disease still kills about 30 percent despite aciclovir.[1][16]

Disposition by syndrome: recurrent labialis or genital HSV managed in primary care or sexual health with episodic or suppressive antivirals; primary disease to sexual health or GUM for STI workup, contact tracing and counselling; eczema herpeticum to ED and dermatology admission for IV aciclovir; neonatal disease to NICU and paediatric infectious diseases with long-term follow-up; HSV keratitis for same-day ophthalmology; HSV encephalitis to ED with neurology or infectious diseases, ICU if obtunded; resistant disease to infectious diseases with susceptibility testing. Safety-net every patient to return for lesions persisting beyond 2–3 weeks, increasing frequency, widespread spread, visual change, neurological symptoms, genital symptoms in pregnancy, or any new vesicle or fever in a neonate.[5][6]

The mantra, and the memory device

[1] [6]

The mantra: grouped vesicles on an erythematous base, PCR to confirm, aciclovir-valaciclovir-famciclovir by timing — and never incise the whitlow, never steroid the dendrite, never wait for the PCR in encephalitis, never send a vesiculating neonate home.[1][5]

Ward-round test — three stems, thirty seconds each

Stem 1 — the swollen bleeding gums (answer)

A 3-year-old has two days of high fever, drooling and refusal to drink, with swollen bleeding gums and vesicles then ulcers on the tongue, buccal mucosa and lips. What is it, and what is the first move? Model: This is primary herpetic gingivostomatitis (HSV-1) — the swollen bleeding gingivae with vesicles and ulcers distinguish it from hand-foot-and-mouth (which has palm and sole lesions) and herpangina (posterior oropharynx only). The acute danger is dehydration, so the first move is analgesia, soft diet and oral rehydration; oral aciclovir within 72 hours shortens symptoms by 1–3 days, with IV aciclovir reserved for severe dehydration, inability to swallow or immunodeficiency. Confirm with HSV PCR if atypical.[12][24]

Stem 2 — the painful red eye (answer)

A 35-year-old has a unilateral painful red eye, photophobia and blurred vision. Fluorescein under cobalt-blue shows a branching epithelial defect. What must you NOT do, and what do you do? Model: This is HSV epithelial keratitis — a dendritic ulcer with terminal end bulbs. You must NOT give topical corticosteroid monotherapy — it converts a dendrite into a geographic ulcer and risks corneal melt. The move is same-day ophthalmology and topical antiviral (ganciclovir 0.15 percent gel or aciclovir 3 percent ointment five times daily), with oral valaciclovir added for stromal disease. The reduced corneal sensation supports the diagnosis.[22]

Stem 3 — the immunocompromised ulcer that will not heal (answer)

A 42-year-old with HIV and CD4 of 80 has a large, chronic, verrucous perianal ulcer unresponsive to 12 days of oral aciclovir 400 mg five times daily. What is happening, and what is the drug? Model: This is aciclovir-resistant HSV — thymidine-kinase (UL23) mutants in a severely immunocompromised host, failing adequate-dose aciclovir. Escalating the aciclovir dose will not work because the resistance is activation-level. Switch to IV foscarnet 40 mg/kg every 8–12 hours with hydration and renal monitoring, biopsy to confirm HSV and exclude other causes, and send susceptibility testing. Cidofovir is the alternative.[15]

References

1. [1]Zhu S, Viejo-Borbolla A. Pathogenesis and virulence of herpes simplex virus Virulence, 2021.PMID 34676800
2. [2]Su D, Han L, Shi C, et al. An updated review of HSV-1 infection-associated diseases and treatment, vaccine development, and vector therapy application Virulence, 2024.PMID 39508503
3. [3]Groves MJ. Genital Herpes: A Review Am Fam Physician, 2016.PMID 27281837
4. [4]Van Wagoner N, Qushair F, Johnston C. Genital Herpes Infection: Progress and Problems Infect Dis Clin North Am, 2023.PMID 37105647
5. [5]Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021 MMWR Recomm Rep, 2021.PMID 34292926
6. [6]Cole S. Herpes Simplex Virus: Epidemiology, Diagnosis, and Treatment Nurs Clin North Am, 2020.PMID 32762854
7. [7]Damour A, Garcia M, Seneschal J, et al. Eczema Herpeticum: Clinical and Pathophysiological Aspects Clin Rev Allergy Immunol, 2020.PMID 31836943
8. [8]Wang V, Boguniewicz J, Boguniewicz M, et al. The infectious complications of atopic dermatitis Ann Allergy Asthma Immunol, 2021.PMID 32771354
9. [9]Hodara E, Ong PY. The Genetics of Eczema Herpeticum Clin Rev Allergy Immunol, 2022.PMID 36114947
10. [10]Wu IB, Schwartz RA. Herpetic whitlow Cutis, 2007.PMID 17674583
11. [11]Betz D, Fane K. Herpetic Whitlow 2026.PMID 29494001
12. [12]Amin N, Darcey J. Primary gingivostomatitis and herpetic whitlow Br Dent J, 2023.PMID 37059770
13. [13]Mirfazaelian H, Daneshbod Y. Herpes gladiatorum Emerg Med J, 2013.PMID 23413153
14. [14]Minichiello JM, Fleming ST, Olson K, et al. Herpes Gladiatorum in College-Aged Wrestler Ann Emerg Med, 2024.PMID 39428193
15. [15]Schalkwijk HH, Snoeck R, Andrei G. Acyclovir resistance in herpes simplex viruses: Prevalence and therapeutic alternatives Biochem Pharmacol, 2022.PMID 36309081
16. [16]Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections Semin Perinatol, 2018.PMID 29544668
17. [17]Hammad WAB, Konje JC. Herpes simplex virus infection in pregnancy - An update Eur J Obstet Gynecol Reprod Biol, 2021.PMID 33581405
18. [18]Mancini A, Inchingolo AM, Marinelli G, et al. Topical and Systemic Therapeutic Approaches in the Treatment of Oral Herpes Simplex Virus Infection: A Systematic Review Int J Mol Sci, 2025.PMID 40943411
19. [19]James C, Harfouche M, Welton NJ, et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016 Bull World Health Organ, 2020.PMID 32514197
20. [20]Harfouche M, AlMukdad S, Alareeki A, et al. Estimated global and regional incidence and prevalence of herpes simplex virus infections and genital ulcer disease in 2020: mathematical modelling analyses Sex Transm Infect, 2025.PMID 39658199
21. [21]Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes N Engl J Med, 2004.PMID 14702423
22. [22]Ahmad B, Gurnani B, Patel BC Herpes Simplex Keratitis 2026.PMID 31424862
23. [23]American College of Obstetricians and Gynecologists. Management of Genital Herpes in Pregnancy: ACOG Practice Bulletinacog Practice Bulletin, Number 220 Obstet Gynecol, 2020.PMID 32332414
24. [24]Coppola N, Cantile T, Canfora F, et al. Supportive care and antiviral treatments in primary herpetic gingivostomatitis: a systematic review Clin Oral Investig, 2023.PMID 37733027